Annals of Surgical Oncology 9:869-874 (2002)
© 2002 Society of Surgical Oncology
Periampullary Pancreatic Somatostatinoma
Michael G. House, MD,
Charles J. Yeo, MD and
Richard D. Schulick, MD
From the Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland.
Correspondence: Address correspondence and reprint requests to: Richard D. Schulick, MD, The Johns Hopkins Hospital, 600 N. Wolfe St., Blalock 657, Baltimore, MD 21287; Fax: 410-614-9882; E-mail: rschulick@ jhmi.edu.
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ABSTRACT
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Background: Somatostatinomas involving the gastrointestinal tract are extremely rare neoplasms that typically present with indolent, nonspecific symptoms in the absence of systemic neuroendocrine manifestations that characterize the somatostatinoma syndrome. Because of a relatively large size at the time of presentation (average diameter of 5 cm) and common location within the head of the pancreas, the Whipple procedure (pancreaticoduodenectomy) serves as the predominant modality for curative and palliative surgical approaches.
Methods: Two cases of somatostatinoma involving the minor duodenal papilla with concomitant pancreatic divisum were reviewed, with a general overview of this unique islet cell tumor.
Results: Unlike typical somatostatinomas, these two tumors were subcentimeter in size but were associated with synchronous regional metastasis.
Conclusions: Somatostatinomas are often associated with regional and/or portal metastases at the time of diagnosis, and only 60% to 70% of surgical cases result in complete tumor resection. Predictors of an unfavorable prognosis include size >3 cm, poor cytological differentiation, regional and/or portal metastasis, and incomplete surgical resection. Even in the presence of synchronous metastases, the 5-year overall survival for patients with somatostatinoma is approximately 40%. Currently, there are no clinical trials demonstrating significant improvement in survival with the use of adjuvant therapy.
Key Words: Somatostatinoma • Pancreas • Islet cell • Neuroendocrine • Whipple procedure • Pancreaticoduodenectomy
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INTRODUCTION
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Only 2500 new cases of pancreatic islet cell tumors are diagnosed each year (mostly discovered incidentally on radiographical imaging), and nearly half of these cases are associated with a functional syndrome due to hormonal secretion. Since 1974, functional neuroendocrine tumors of the gastroenteropancreatic tract have been classified according to the major secretory hormone attributable to each tumor: insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, and so on.1 Tumors of the endocrine pancreas and gastrointestinal tract that secrete excessive amounts of somatostatin are thus classified as somatostatinomas, even though 10% of such tumors secrete other humoral factors, including glucagon, gastrin, vasoactive intestinal polypeptide, insulin, calcitonin, and adrenocorticotropic hormone.2–4 Somatostatinomas are typically large, solitary, malignant tumors arising from the head of the pancreas, and they are often discovered with either lymph node or liver metastases at the time of diagnosis or surgical exploration.
Since the first two case reports of somatostatinomas in 1977, followed by the characterization of the clinical syndrome in 1979, fewer than 200 cases of somatostatinoma have been reported in the medical and surgical literature.5–8 This rare tumor, with an estimated annual incidence of 1 in 40 million, may arise within the pancreas itself (56% of reported cases) or from extrapancreatic sites, including the duodenum, ampulla, jejunum, or cystic duct.5,9
In 1985, Malone et al.10 were the first to present a case of a functional somatostatinoma originating from the minor duodenal papilla that presented with systemic neuroendocrine features. In this article, two cases of nonfunctional ampullary somatostatinomas presenting to The Johns Hopkins Hospital within a 1-month period are described, in addition to a general overview of gastrointestinal somatostatinomas.
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CASE REPORTS
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The first patient was a 61-year-old white woman who presented after an episode of acute pancreatitis unassociated with etiological factors recognized on laboratory, radiographical (i.e., computed tomographic [CT] scan), or endoscopic (i.e., endoscopic retrograde cholangiopancreatography [ERCP]) studies. Of interest, over the several months preceding this episode, the patient had developed progressive postprandial epigastric pain, steatorrhea, new-onset non–insulin-dependent diabetes mellitus, and a 10-kg weight loss. Her medical and surgical histories were remarkable for a remote laparoscopic cholecystectomy. A family history of colon and head/neck cancer was also present. Her only medications included omeprazole, an oral hypoglycemic, and an inhaled bronchodilator. The patient’s physical examination was notable only for mild, vague tenderness over the right upper abdominal quadrant. No abnormalities were present on laboratory studies, including a complete hepatic panel. A follow-up ERCP was performed 1 month after the original episode of pancreatitis. This revealed a dilated pancreatic duct with filling defects in the setting of a pancreas divisum (Fig. 1) . An endoscopic ultrasound (EUS) was also performed at the time of ERCP and demonstrated only nonspecific hypoechoic changes within the head of the pancreas in addition to the dilated pancreatic duct. To further investigate these indeterminate findings on EUS, the patient underwent a repeat dual-phase CT scan of the abdomen, incorporating multidetector three-dimensional reconstructions. This study revealed a small (<1-cm) nodular area arising from the ampulla with secondary pancreatic ductal dilatation. In addition, slight irregularity was evident within the head of the pancreas (Fig. 2). Further assessment of these findings was pursued with a repeat EUS, and a fine-needle aspiration was directed at the suspicious periampullary mass arising from the minor papilla. Cytopathology confirmed well-differentiated neuroendocrine tumor cells with positive immunocytochemical staining for somatostatin. A preoperative serum somatostatin level was measured at 16 pg/mL (reference range, 10–22 pg/mL), consistent with the absence of a clinical neuroendocrine syndrome. At laparotomy, a duodenotomy was initially performed in an attempt to perform a local resection. When the duodenum was entered, a firm mass was palpated within the origins of the minor papilla, with background firmness involving the pancreatic head. Given these gross findings, a pylorus-preserving pancreaticoduodenectomy (Whipple procedure) was performed. No operative complications were encountered, and the patient was discharged home with complete resolution of her presenting symptoms after an uneventful 7-day postoperative course. Pathologic examination of the Whipple specimen demonstrated an 8-mm malignant well-differentiated somatostatinoma arising from the minor papilla (Fig. 3). All surgical margins were negative; however, metastatic neuroendocrine tumor was discovered in 4 of the 21 resected regional lymph nodes. Except for somatostatin, no other selective immunostaining was detected (i.e., gastrin, glucagon, insulin, and so on) (Fig. 4).
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FIG. 1. Endoscopic retrograde cholangiopancreatography showing diffuse dilatation of the main pancreatic duct arising from the minor ampulla, consistent with pancreatic divisum. Accessory ductal collateralization and dilatation are present. No ductal calcifications are evident.
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FIG. 2. (A and B) Dual-phase computed tomographic scan of the upper abdomen, demonstrating a focal nodular prominence originating from the second portion of the duodenum at the level of the ampulla (arrow in A). (B) confirms the presence of a diffusely dilated pancreatic duct with atrophic changes involving the body and tail. Cystic changes are noted within the liver.
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FIG. 3. (A and B) Gross surgical specimen of the second portion of the duodenum and adjacent pancreas after a Whipple procedure. (A) The pancreatic divisum, characterized by the confluence of the common bile duct with the accessory pancreatic duct at the major papilla (MAJOR). PD represents the main pancreatic duct at the minor papilla. (B) An .8-cm somatostatinoma originating at the minor ampulla.
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FIG. 4. (A and B) Histological sections (magnification, x100) of a periampullary pancreatic somatostatinoma. (A) Standard hematoxylin and eosin staining of a pancreatic islet cell tumor. (B) Cytoplasmic somatostatin immunostaining with a specific monoclonal antibody (Dako, Carpinteria, CA) at a 1/5000 dilution.
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The second patient was a 71-year-old healthy white man who presented with a 1-month history of postprandial nausea associated with epigastric pain radiating to the back. After negative serological studies and an unremarkable physical examination, the patient was evaluated with esophagogastroduodenoscopy, and a bulging prominence at the minor papilla was detected. ERCP with cannulation of the minor papilla failed to visualize the pancreatic duct. EUS revealed severe pancreatic ductal dilatation to 1.5 cm, with ductal thickening, but fine-needle aspiration of this irregular zone was nondiagnostic. A CT scan clearly demonstrated the aforementioned minor papillary prominence and ductal dilatation; however, no discrete mass within the pancreas was evident. Because of nonvisualization of the pancreatic duct on ERCP, the patient underwent a magnetic resonance cholangiopancreatography (Fig. 5), which revealed abrupt termination of a dilated pancreatic duct approximately 2 cm from the ampulla. For these radiographical findings, the patient underwent surgical exploration, and a pylorus-preserving Whipple procedure was performed without complications. After surgery, the patient recovered uneventfully and was discharged home on the sixth postoperative day. Final histopathology of the resected specimen demonstrated a 1.6-cm well-differentiated malignant neuroendocrine tumor arising in the minor ampulla, associated with pancreas divisum. Metastatic disease was found in 3 of 17 resected lymph nodes. Immunohistochemical staining revealed the presence of somatostatin-secreting cells.
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FIG. 5. Magnetic resonance cholangiopancreatography revealing diffuse dilatation of the pancreatic duct to 1.5 cm in diameter with abrupt termination near the level of the ampulla (arrow).
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DISCUSSION
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The median age of patients diagnosed with somatostatinoma is 54 years, with a reported range of 30 to 84 years.11 Whereas pancreatic somatostatinomas show a slight female preponderance (67%), extrapancreatic sites of disease are found more often in men.11 Given the extremely rare incidence, there are only a few clear risk factors for somatostatinoma. Of patients who develop somatostatinomas, 45% of cases are affiliated with multiple endocrine neoplasia type I.9,12 Extrapancreatic somatostatinomas, especially those appearing in the duodenum or jejunum, have been associated with neurofibromatosis.12,13
The classic syndrome of hyperglycemia, cholelithiasis, steatorrhea, and hypochlorhydria is present in only a small proportion of patients presenting with somatostatinoma. More commonly, patients complain of nonspecific symptoms such as vague abdominal pain, weight loss, or a change in bowel habits regardless of their plasma somatostatin level (reference range, 10–22 pg/mL). Consequently, a preoperative diagnosis of a somatostatin-secreting islet cell tumor is extremely difficult unless there is a high clinical index of suspicion on the basis of symptomatology. When present, the systemic neuroendocrine phenomena of the somatostatinoma syndrome result from excessive tumor secretion of somatostatin, a cyclic tetradecapeptide, which has direct inhibitory effects on the release of gastrointestinal hormones, including insulin, cholecystokinin, pancreatic enzymes, and gastrin.5,14 Excessive circulating levels of somatostatin can be associated with somatostatinomas arising either within the pancreas or in extrapancreatic sites, especially when their size exceeds 4 cm in diameter.9,15 Patients with nonfunctional, extrapancreatic somatostatinomas are more likely to present with symptoms related to the space-occupying nature of the tumor, such as biliary or enteric obstruction.
In the absence of discrete symptoms or physical findings, most gastrointestinal somatostatinomas are diagnosed histopathologically after surgical resection for a pancreatic or extrapancreatic mass. On histological examination, somatostatinomas appear as well-differentiated islet cell tumors that stain positive for somatostatin (Fig. 4). Psammoma bodies can be found uniquely in extrapancreatic somatostatinomas.15 Delta granules, characteristic of islet D cells, are detected only by electron microscopy.
In some cases, radiographical work-up reveals a pancreatic mass suggestive of an islet cell tumor, and a subsequent increased somatostatin level may suggest the diagnosis. Current CT and magnetic resonance imaging techniques have a sensitivity of >95% for detecting pancreatic and abdominal masses >2 cm. Because of their large size (average diameter, 5 cm; range, .5–10 cm) and solitary nature, somatostatinomas usually are well localized radiographically before surgical exploration.9,15 Given the fact that approximately 80% of all gastroenteropancreatic endocrine tumors, including somatostatinomas, express somatostatin receptors, Octreoscan (Mallinckrodt Medical, St. Louis, MO) with an indium-111–labeled octreotide analog has proven reliable for detecting and staging somatostatinomas.16,17 Within the pancreas, nearly 60% of somatostatinomas arise within the head, whereas 30% are found within the tail.2,11 The most common extrapancreatic site of somatostatinoma is the duodenum, followed by the ampulla of Vater.5 Other sites include the jejunum and cystic duct. It is interesting to note that extrapancreatic somatostatinomas are usually smaller (<4 cm) and are associated with less malignant potential than their pancreatic counterparts.9,18 Clinically, the somatostatinoma syndrome is observed with extrapancreatic sites very infrequently.9 In cases of duodenal somatostatinoma, the mass is often discovered on upper endoscopy and later diagnosed on histopathology of the biopsied specimen. Recently, EUS with fine-needle aspiration has emerged as a reliable method to diagnose islet cell tumors before surgery.19
The mainstay of treatment for gastrointestinal somatostatinomas, with their nearly universal malignant potential, is surgical resection. Because of their large size and common location either within the head of the pancreas or the duodenum, pancreaticoduodenectomy (Whipple procedure) is the most commonly performed surgical procedure for somatostatinoma. Although 70% of cases of somatostatinoma have synchronous metastatic disease involving the liver and/or regional lymph nodes, surgical intervention should be explored.20,21 Even in the setting of metastatic or locally advanced disease, it may make sense to perform debulking procedures, because this may lead to improved survival or quality of life, especially in the setting of hormonal excess.22 Palliation of obstruction, hormonal excess, and pain from resection clearly benefits some patients. When 
90% of the tumor burden is resected, patients can expect to achieve prolonged relief of symptoms for longer than 2 years.23,24 In patients with liver metastases not amenable to resection or ablation, hepatic artery embolization or chemoembolization can be an effective therapy for symptomatic palliation.22
The treatment of choice for somatostatinoma is surgical resection, when possible, because this is the only currently available intervention that can afford cure. Unfortunately, only 65% of somatostatinomas that present for surgical exploration result in complete resection of all tumor detected locally or regionally.2 Lack of complete resection inarguably decreases overall survival in patients with somatostatinoma. Additional factors that portend an unfavorable prognosis are lymph node involvement, poor tumor differentiation, nonfunctional status, and the presence of metastatic disease.21,25 Tumor size >3 cm also affords a poor prognosis because 75% of such tumors are associated with gross or occult liver metastases, compared with 35% for tumors <3 cm.21,26,27 The overall 5-year survival for patients with somatostatinoma is 60%. In the presence of liver metastases, the survival rate is 40% at 5 years. In the absence of liver or lymph node metastases, the 5-year survival rate is 100%.13
Because supportive data are lacking, adjuvant therapy for somatostatinoma is not advocated after complete resection. In cases of locally unresectable or metastatic somatostatinoma, chemoradiotherapy has been used in the past despite the fact that neuroendocrine tumors in general are quite resistant to radiotherapy and are only modestly responsive to current chemotherapy agents. Only a few randomized trials have studied the tumor response rates of islet cell tumors to a small consortium of chemotherapy regimens. To date, the best response rate (69%) and survival advantage (median survival, 2.2 years) have been observed with a regimen involving streptozocin combined with doxorubicin.28 Interferon alfa and dimethyltriazeno-imidazole as single agents have not shown any benefit in larger trials of islet cell tumor therapy, despite encouraging anecdotal reports.29,30 Even though there is no clear overall survival benefit to delivering chemotherapy either systemically or through selective hepatic artery embolization, patients with advanced disease experience symptomatic relief with both of these modalities.
For patients with rapidly progressive somatostatinoma, with either a poorly controlled neuroendocrine syndrome refractory to supportive medical therapy or with debilitating symptoms attributable to bulk disease, attempts at palliation may require combination medical and surgical intervention, as outlined previously. In addition, the somatostatin analog octreotide may afford significant assistance in reducing tumor hormone secretion and retarding tumor growth.31
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CONCLUSION
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Somatostatinomas are exceedingly rare neoplasms involving the pancreas or alimentary tract. These malignant islet cell tumors are often associated with regional and systemic metastases at the time of diagnosis. Like the two cases reported previously, these tumors are seldom associated with the classic tetrad of clinical manifestations and typically present with vague, indolent symptoms that delay aggressive diagnostic work-up. Regardless of the stage of disease, a surgical approach to somatostatinomas combined with medical support should be considered for curative and palliative goals.
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Acknowledgments
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The authors thank Dr. Anirban Maitra, Johns Hopkins Department of Pathology, for his assistance with the immunohistochemistry studies of the pancreatic somatostatinoma.
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Footnotes
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Two cases of periampullary somatostatinoma arising within the minor duodenal papilla in patients with pancreas divisum are presented, with a general overview of the diagnosis and management of these rare peculiar tumors.
Received for publication March 7, 2002.
Accepted for publication July 10, 2002.
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ABSTRACT
INTRODUCTION
